1. Field of the Invention
The present invention relates to phenylpiperazine derivatives and phenylpiperidine derivatives having integrin xcex1vxcex23 antagonistic activity, and pharmaceuticals comprising the same.
2. Background Art
In recent years, cell adherent proteins have been enthusiastically studied to apply proteins or the like involved in the mechanism of the regulation of cell adhesion to pharmaceuticals. Regarding interaction between platelet membrane glycoprotein GP IIb/IIIa and fibrinogen which plays an important role in platelet aggregation, extensive studies have already been carried out in various countries of the world, with consideration of clinical tests. For example, ReoPro having platelet aggregation activity has been clinically used.
Integrin xcex1vxcex23 which interacts with various extracellular matrix or cell adhesive proteins, has been proved to play an important role in the progress of arterial sclerosis, arterialization, and solid tumors. For this reason, regarding integrin xcex1vxcex23 antagonist as well, animal experiments have been initiated with consideration of clinical tests in various countries. Attention has been drawn to this by chemical and biochemical researchers, as well as by medical care-related persons engaged in basic research (Journal of Cardiac Society of U.S.A., Circulation, I-668, 1997, DuPont-Merck).
Up to now, small molecules having integrin xcex1vxcex23 antagonistic activity have been reported (WO 95/32710 (Merck), WO 96/37492 (DuPont-Merck), WO 97/01540 (SKB), WO 97/08145 (Searle and Co.), WO 97/23451 (Merck), WO 7/23480 DuPont-Merck), WO 97/24119(SKB), WO 97/33887 (DuPont-Merck), WO 97/36858 (Searle and Co.), WO 97/36859 (Searle and Co.), WO 97/36860 (Searle and Co.), WO 97/36861 (Searle and Co.), WO 97/36862 (Searle and Co.), and EP 0796855 (Hoechst).
The present inventors have found that a certain group of derivatives have potent integrin xcex1vxcex23 antagonistic activity. The present inventors have also found that a certain group of derivatives have potent GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity.
Accordingly, an object of the present invention is to provide a compound having integrin xcex1vxcex23 antagonistic activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity.
Another object of the present invention is to provide a therapeutic agent for integrin xcex1vxcex23-mediated diseases and an agent for inhibiting a platelet aggregation.
According to one aspect of the present invention, there is provided a compound represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: 
wherein
A represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which is optionally substituted by C1-6 alkyl or amino optionally substituted by C1-6 alkyl, aralkyl, C1-6 alkoxycarbonyl, or aralkyloxycarbonyl, or which is optionally condensed with other saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring to form a bicyclic group, wherein the carbocyclic group and the heterocyclic group are optionally substituted by C1-6 alkyl or amino optionally substituted by C1-6 alkyl, aralkyl, C1-6 alkoxycarbonyl, or aralkyloxycarbonyl,
or a group represented by formula 
wherein
R1, R2, and R3, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or nitrile, or R1 and R2 may together form group xe2x80x94(CH2)rxe2x80x94, wherein r is 4 or 5, or group xe2x80x94(CH2)2xe2x80x94Oxe2x80x94(CH2)2xe2x80x94, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
X and Z, which may be the same or different, represent CH or N;
R4 represents C1-6 alkyl, C1-6 alkoxy, a halogen atom, amino, nitro, hydroxyl, or an oxygen atom, wherein C1-6 alkyl and C1-6 alkoxy are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R5 represents C1-6 alkyl, C1-6 alkoxy, a halogen atom, amino, nitro, or hydroxyl, wherein C1-6 alkyl and C1-6 alkoxy are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
Q represents  greater than Cxe2x95x90O,  greater than CH2,  greater than CHR10, or  greater than CHOR10 wherein R10 represents C1-6 alkyl;
R6 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, or aralkyl, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R7 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or amino, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl, and amino is optionally substituted by C1-6 alkyl, C1-6 alkoxycarbonyl, benzenesulfonyl in which the phenyl portion is optionally substituted by C1-6 alkyl, or aralkyloxycarbonyl;
R8 represents a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aralkyl, or amino, wherein C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl, and the amino is optionally substituted by C1-6 alkyl, C1-6 alkoxycarbonyl, alkylsulfonyl, benzenesulfonyl in which the phenyl portion is optionally substituted by C1-6 alkyl, phenyl optionally condensed with the phenyl portion, carboxyl, hydroxyl, nitro, amino, saturated or unsaturated five- to seven-membered carbocyclic group or heterocyclic group, C1-6 alkylamino or a halogen atom, aralkyloxycarbonyl, or group xe2x80x94C(xe2x95x90O)xe2x80x94(CH2 )sxe2x80x94C(xe2x95x90O)xe2x80x94NHR11 wherein s is an integer of 0 to 4 and R11 represents a hydrogen atom or hydroxyl;
R9 represents a hydrogen atom or C1-6 alkyl;
m is an integer of 0 to 5;
n is an integer of 0 to 4;
p is 2 or 3; and
q is 0 or 1.
The compounds according to the present invention are useful in the treatment of integrin xcex1vxcex23-mediated diseases. The compounds according to the present invention are also useful as an agent for inhibiting platelet aggregation.
Compound
As used herein, the term xe2x80x9cC1-6 alkylxe2x80x9d and xe2x80x9cC1-6 alkoxyxe2x80x9d as a group or a part of a group respectively mean straight chain, branched chain, or cyclic alkyl and alkoxy having 1 to 6, preferably 1 to 4 carbon atoms.
As used herein, the term xe2x80x9cC2-6 alkenylxe2x80x9d and xe2x80x9cC2-6 alkynylxe2x80x9d as a group or a part of a group respectively mean straight chain, branched chain, or cyclic alkenyl or alkynyl having 2 to 6, preferably 2 to 4 carbon atoms.
Examples of C1-6 alkyl include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, cyclopentyl, n-hexyl, and cyclohexyl.
Examples of C1-6 alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, and t-butoxy.
Examples of C2-6-alkenyl include allyl.
Examples of C2-6 alkynyl include 2-propynyl and ethinyl.
Examples of saturated or unsaturated five- to seven-membered carbocyclic groups include phenyl.
As used herein, the term xe2x80x9csaturated or unsaturated five- to seven-membered heterocyclic ringxe2x80x9d means a five- to seven-membered heterocyclic ring containing at least one hetero-atom selected from oxygen, nitrogen, and sulfur atoms, preferably a five- to seven-membered heterocyclic ring containing one nitrogen atom, more preferably a five- or six-membered heterocyclic ring containing one nitrogen atom. The term xe2x80x9chetero-atomxe2x80x9d used herein means an oxygen, nitrogen, or sulfur atom. Examples of saturated or unsaturated five- to seven-membered heterocyclic groups include pyrimidyl, 1,4,5,6-tetrahydropyrimidyl, imidazolyl, tetrahydro-[1,3]diazepinyl, and imidazolidinyl.
The saturated or unsaturated heterocyclic group may be condensed with another saturated or unsaturated heterocyclic ring to form a bicyclic ring. Such condensed cyclic groups include benzimidazolyl, naphthyl, and azabenzimidazolyl.
As used herein, the term xe2x80x9caralkylxe2x80x9d as a group or a part of a group means a C1-6 alkyl, preferably C1-4 alkyl, substituted by a saturated or unsaturated five- to seven-membered carbocyclic group or heterocyclic group. Examples of aralkyls include benzyl and phenethyl.
The term xe2x80x9chalogen atomxe2x80x9d means a fluorine, chlorine, bromine, or iodine atom.
Both X and Z preferably represent nitrogen.
The five- to seven-membered heterocyclic group represented by A is preferably a five- or six-membered heterocyclic group.
The bicyclic heterocyclic group represented by A is preferably a nine- or ten-membered heterocyclic group, more preferably a nine- or ten-membered heterocyclic group containing two or three nitrogen atoms.
Preferably, A is a group represented by formula 
wherein
Het represents a saturated or unsaturated five- to seven-membered heterocyclic group containing two nitrogen atoms, which is optionally substituted by C1-6 alkyl or amino optionally substituted by C1-6 alkyl, aralkyl, C1-6 alkoxycarbonyl, or aralkyloxycarbonyl, or which is optionally condensed with another saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring, preferably another saturated or unsaturated five- to seven-membered carbocyclic ring or heterocyclic ring containing one nitrogen atom, to form a bicyclic group, wherein the carbocyclic group and the heterocyclic group are optionally substituted by C1-6 alkyl or amino optionally substituted by C1-6 alkyl, aralkyl, C1-6 alkoxycarbonyl or aralkyloxycarbonyl. 
wherein
R21, R22, and R23, which may be the same or different, represent a hydrogen atom, C1-6 alkyl, C2-6 alkenyl, or aralkyl, wherein C1-6 alkyl, C2-6 alkenyl, and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl, or
R21 and R23 may together form
group xe2x80x94(CH2)4xe2x80x94,
group xe2x80x94(CH2)3xe2x80x94,
group xe2x80x94CHR24CH2CH2xe2x80x94wherein R24 represents C1-6 alkyl or amino optionally substituted by C1-6 alkyl, C1-6 alkoxycarbonyl, aralkyl, or aralkyloxycarbonyl,
group xe2x80x94CH2CHR24CH2xe2x80x94 wherein R24 is as defined above,
group xe2x80x94CH2CH2xe2x80x94,
group xe2x80x94CHR24CH2xe2x80x94 wherein R24 is as defined above,
group xe2x80x94CR25xe2x95x90CR26xe2x80x94 wherein R25 and R26, which may be the same or different, represent a hydrogen atom or C1-6 alkyl, or R25 and R26 may together form xe2x80x94CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,xe2x80x94Nxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94CHxe2x95x90Nxe2x80x94CHxe2x95x90CHxe2x80x94, or
R21 and R23 may together form
group xe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94,
group xe2x95x90CHxe2x80x94CHxe2x95x90Nxe2x80x94, or
group xe2x95x90CHxe2x80x94Nxe2x95x90CHxe2x80x94, and
R22 may represent a single bond between R21 and the nitrogen atom attached to R21.
In the compound represented by formula (I), one or more hydrogen atoms in the following portion may be substituted by R4. 
When m is zero (0), R4 is absent. When m is 1, one hydrogen atom in the above portion is substituted by R4. When m is 2 or more, two or more hydrogen atoms in the above portion are substituted by R4. In this case, the substituents may be the same or different. When R4 represents an oxygen atom, the bond between the R4 and the above portion is a double bond. m is preferably an integer of 0 to 2.
In the compound represented by formula (I), one or more hydrogen atoms in the phenylene portion may be substituted by R5.
When n is zero (0), R5 is absent. When n is 1, one hydrogen atom in the phenylene portion is substituted by R5. When n is 2 or more, two or more hydrogen atoms in the phenylene portion are substituted by R5. In this case, the substituents may be the same or different. n is preferably an integer of 0 to 2.
Q preferably represents  greater than Cxe2x95x90O or  greater than CH2.
R6 preferably represents a hydrogen atom, C1-6 alkyl, preferably methyl, propyl, or cyclopropylmethyl, or aralkyl, preferably benzyl or phenethyl.
R7 preferably represents a hydrogen atom, C2-6 alkynyl, or optionally substituted amino, more preferably a hydrogen atom or C2-6 alkynyl.
When q is zero (0), xe2x80x94(CHR7)qxe2x80x94 represents a single bond. q is preferably 1.
R8 preferably represents a hydrogen atom, C2-6 alkynyl, or optionally substituted amino, more preferably a hydrogen atom or optionally substituted amino.
The phenyl portion of benzenesulfonyl as a substituent of amino represented by R7 and R8 may be substituted by 1 to 3 C1-6alkyl which may be the same or different.
The aralkyl portion of aralkyloxycarbonyl as a substituent of amino represented by R7 and R8 may be benzyl or phenethyl.
s in group xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)sxe2x80x94C(xe2x95x90O)xe2x80x94NHR11 as a substituent of amino represented by R7 and R8 is preferably an integer of 1 to 3, more preferably 1 or 2.
A group of preferred compounds represented by formula (I) are those wherein
X and Z both represent N;
A represents a group of formula 
xe2x80x83wherein
R21, R22, and R23 are as defined above;
Q represents  greater than Cxe2x95x90O or  greater than CH2;
R6 represents a hydrogen atom, C1-6 alkyl, or aralkyl, wherein C1-6 alkyl and aralkyl are optionally substituted by a halogen atom, C1-6 alkoxy, amino, or hydroxyl;
R7 represents a hydrogen atom or C2-6 alkynyl;
R8 represents a hydrogen atom or amino optionally substituted by C1-6 alkyl; C1-6 alkoxycarbonyl; benzenesulfonyl in which the phenyl portion is optionally substituted by C1-6 alkyl; aralkyl; aralkyloxycarbonyl; or group xe2x80x94C(xe2x95x90O)xe2x80x94(CH2)sxe2x80x94C (xe2x95x90O)xe2x80x94NHR11 wherein s is an integer of 0 to 4 and R11 represents a hydrogen atom or hydroxyl;
m and n are each an integer of 0 to 2; and
q is 1.
Of the compounds represented by formula (I), the following compounds are particularly preferred:
(1) t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(2) (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(3) (2S)-benzenesulfonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoyl-amino]-propionic acid;
(4) t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-yl)-[1,4]diazepan-1-yl}-benzoylamino]-propionate;
(5) (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-yl)-[1,4]diazepan-1-yl}-benzoylamino]-propionic acid;
(6) (2S)-benzenesulfonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-[1,4]diazepan-1-yl}-benzoylamino]-propionic acid;
(7) t-butyl (2S)-benzenesulfonylamino-3-[4-{3-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(8) (2S)-benzenesulfonylamino-3-[4-{3-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(9) (2S)-benzenesulfonylamino-3-[4-{3-methyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(10) t-butyl (2S)-benzenesulfonylamino-3-[4-{(3R)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(11) (2S)-benzenesulfonylamino-3-[4-{(3R)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(12) (2S)-benzenesulfonylamino-3-[4-{(3R)-methyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(13) t-butyl (2S)-benzenesulfonylamino-3-[4-{(3S)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(14) (2S)-benzenesulfonylamino-3-[4-{(3S)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(15) (2S)-benzenesulfonylamino-3-[4-{(3S)-methyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(16) t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(1H-benzimidazol-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(17) (2S)-benzenesulfonylamino-3-[4-{4-(1H-benzimidazol-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(18) ethyl (3S)-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-pent-4-ynate;
(19) (3S)-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-pent-4-ynic acid;
(20) t-butyl (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzylamino]-propionate;
(21) (2S)-benzenesulfonylamino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzylamino]-propionic acid;
(22) (2S)-benzenesulfonylamino-3-{4-[4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl]-benzylamino}-propionic acid;
(23) (2S)-benzenesulfonylamino-3-[methyl-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzyl]-amino]-propionic acid;
(24) (2S)-benzenesulfonylamino-3-[methyl-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzyl]-amino]-propionic acid;
(25) (2S)-benzenesulfonylamino-3-[benzyl-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzyl]-amino]-propionic acid;
(26) (2S)-benzenesulfonylamino-3-[benzyl-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzyl]-amino]-propionic acid;
(27) t-butyl (2S)-benzyloxycarbonylamino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(28) (2S)-benzyloxycarbonylamino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(29) (2S)-amino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(30) (2S)-benzyloxycarbonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(31) t-butyl (2S)-benzenesulfonylamino-3-[cyclopropylmethyl-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoyl]-amino]-propionate;
(32) (2S)-benzenesulfonylamino-3-[cyclopropylmethyl-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoyl]-amino]-propionic acid;
(33) (2S)-benzenesulfonylamino-3-[cyclopropylmethyl-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoyl]-amino]-propionic acid;
(34) (2S)-benzenesulfonylamino-3-[4-{4-(amidino)-piperazin-1-yl}-benzoylamino]-propionic acid;
(35) t-butyl (2S)-benzenesulfonylamino-3-[4-{cis-3,5-dimethyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(36) (2S)-benzenesulfonylamino-3-[4-{cis-3,5-dimethyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(37) (2S)-benzenesulfonylamino-3-[4-{cis-3,5-dimethyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(38) t-butyl 3-[4-{4-(1H-benzimidazol-2-yl)-piperazin-1-yl}-benzoylamino]-(2S)-benzyloxycarbonylamino-propionate;
(39) 3-[4-{4-(1H-benzimidazol-2-yl)-piperazin-1-yl}-benzoylamino]-(2S)-benzyloxycarbonylamino-propionic acid;
(40) t-butyl (2S)-benzenesulfonylamino-3-[propyl-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoyl]-amino]-propionate;
(41) (2S)-benzenesulfonylamino-3-[propyl-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoyl]-amino]-propionic acid;
(42) (2S)-benzenesulfonylamino-3-[propyl-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoyl]-amino]-propionic acid;
(43) (2S)-t-butoxycarbonylamino-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(44) t-butyl 2-(benzenesulfonyl-methyl-amino)-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(45) 2-(benzenesulfonyl-methyl-amino)-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(46) 2-(benzenesulfonyl-methyl-amino)-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(47) t-butyl 2-(benzenesulfonyl-hexyl-amino)-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(48) 2-(benzenesulfonyl-hexyl-amino)-3-[4-{4-(pyrimidin-2-yl)-piperazin1-yl}-benzoylamino]-propionic acid;
(49) 2-(benzenesulfonyl-hexyl-amino)-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(50) (2S)-(3-hydroxycarbamoyl-propionylamino)-3-[4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(51) t-butyl (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(52) (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(53) (2S)-benzenesulfonylamino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(54) t-butyl (2S)-benzenesulfonylamino-3-[2-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(55) (2S)-benzenesulfonylamino-3-[2-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(56) (2S)-benzenesulfonylamino-3-[2-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(57) t-butyl (2S)-benzenesulfonylamino-3-[3-chloro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(58) (2S)-benzenesulfonylamino-3-[2-chloro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(59) (2S)-benzenesulfonylamino-3-[3-chloro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(60) t-butyl (2S)-benzenesulfonylamino-3-[2-chloro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(61) (2S)-benzenesulfonylamino-3-[2-chloro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(62) (2S)-benzenesulfonylamino-3-[2-chloro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(63) t-butyl (2S)-benzenesulfonylamino-3-[3-nitro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(64) (2S)-benzenesulfonylamino-3-[2-nitro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(65) 3-[3-amino-2-chloro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-(2S)-benzenesulfonylamino-propionic acid;
(66) t-butyl (2S)-benzyloxycarbonylamino-3-[4-{(3S)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(67) (2S)-benzyloxycarbonylamino-3-[4-{(3S)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(68) (2S)-amino-3-[4-{(3S)-methyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(69) (2S)-benzyloxycarbonylamino-3-[4-{(3S)-methyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(70) t-butyl (2S)-benzenesulfonylamino-3-[3-fluoro-4-{(3S)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(71) (2S)-benzenesulfonylamino-3-[3-fluoro-4-{(3S)-methyl-4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(72) (2S)-benzenesulfonylamino-3-[3-fluoro-4-{(3S)-methyl-4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(73) t-butyl (2S)-benzyloxycarbonylamino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(74) (2S)-benzyloxycarbonylamino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(75) (2S)-amino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(76) (2S)-benzyloxycarbonylamino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(77) t-butyl (2S)-ethylamino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(78) (2S)-ethylamino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(79) (2S)-ethylamino-3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(80) t-butyl (2S)-amino-3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate;
(81) t-butyl 3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-(2S)-(2,4,6-trimethyl-benzenesulfonylamino)-propionate;
(82) 3-[3-fluoro-4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-(2S)-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid;
(83) 3-[3-fluoro-4-{4-(1,4,5,6-tetrahydropyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-(2S)-(2,4,6-trimethyl-benzenesulfonylamino)-propionic acid;
(84) t-butyl (2S)-amino-3-[4-{4-(pyrimidin-2-yl)-piperazin1-yl}-benzoylamino]-propionate;
(85) (2S)-amino-3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid;
(86) ethyl 3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionate; and
(87) 3-[4-{4-(pyrimidin-2-yl)-piperazin-1-yl}-benzoylamino]-propionic acid.
The compounds according to the present invention may form pharmacologically acceptable salts thereof. Such salts include non-toxic salts. Preferred salts include hydrohalogenic acid salts such as hydrochloride salts, hydrobromide salts, or hydroiodide salts; inorganic acid salts such as nitric acid salts, perchloric acid salts, sulfuric acid salts, or phosphoric acid salts; lower alkylsulfonic acid salts such as methanesulfonic acid salts, trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts; arylsulfonic acid salts such as benzenesulfonic acid salts or p-toluenesulfonic acid salts; organic acid salts such as fumaric acid salts, succinic acid salts, citric acid salts, tartaric acid salts, oxalic acid salts, or maleic acid salts; amino acid salts such as glutamic acid salts or aspartic acid salts; alkali metal or alkaline earth metal salts such as sodium salts, potassium salts, and calcium salts; and organic alkali salts such as pyridine salts or triethylamine salts.
The compounds according to the present invention may form solvates (for example, hydrates or ethanolate).
Production of compounds
Compounds represented by formula (I), wherein X and Z both represent nitrogen, may be produced according to the following scheme: 
 less than Step 1 greater than 
An optionally substituted ethyl 4-fluorobenzoate may be reacted with piperazine or homopiperazine which is optionally substituted at the carbon atom(s) (hereinafter referred to simply as xe2x80x9cpiperazine derivativexe2x80x9d) in the presence of a reaction solvent, such as dimethyl sulfoxide or sulfolane (preferably dimethyl sulfoxide), at 50 to 150xc2x0 C., preferably 80 to 120xc2x0 C., to prepare a compound represented by formula (II). In this reaction, an organic base such as diisopropylethylamine may be added as an acid scavenger.
In addition to ethyl 4-fluorobenzoate, other ester compounds, for example, methyl, propyl, butyl, or benzyl ester compounds may be used as the starting compound.
Further, in addition to ethyl 4-fluorobenzoate, other 4-halogenobenzoates which have been substituted at the 4-position, for example, ethyl 4-iodobenzoate and ethyl 4-bromobenzoate, may be used. Among them, the use of ethyl 4-fluorobenzoate is preferred from the viewpoint of yield.
Furthermore, in addition to ethyl 4-fluorobenzoate, optionally substituted 4-fluorobenzonitrile may be used as the starting compound. In this case, in a proper later step, for example, acid hydrolysis or the like may be performed for conversion to a free carboxyl group, thereby producing a compound represented by formula (VI).
In the above scheme, a piperazine derivative, wherein one of the secondary amines has been previously protected, may be used for the production of the compound represented by formula (II). In this case, after a proper reaction step, the protective group may be removed followed by introduction of a new substituent into the secondary amine.
 less than Step 2 greater than 
Group A may be introduced into the free secondary amine in the compound represented by formula (II) to produce a compound represented by formula (III). The Nxe2x80x94C bond between the compound represented by formula (II) and group A may be formed by reacting the compound represented by formula (II) with a reagent, such as optionally modified or substituted 2-bromopyrimidine, 2-chlorobenzimidazole, or 2-methylthio-2-imidazoline, in the presence of a reaction solvent, such as dimethylformamide, dimethyl sulfoxide, sulfolane, pyridine, or methanol, preferably dimethylformamide, at 50 to 1500xc2x0 C., preferably 60 to 120xc2x0 C.
Reagents usable in this step is not limited to those recited herein, and any reagent may be used so far as a carbon atom attached to two nitrogen atoms finally combines with the nitrogen atom in the secondary amine in the piperazine derivative portion to form a single bond.
An organic base, such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, or triethylamine, is preferably added as an acid scavenger from the viewpoint of improving the yield. The addition of 2 to 10 equivalents of diisopropylethylamine is preferred.
In the scheme, the bonding of the benzoic acid portion to the piperazine derivative is followed by the introduction of a basic atomic group, for example, pyrimidine or benzimidazole, into the secondary amine in the piperazine derivative portion. The production process of the compound represented by formula (III) is not always limited to the above process. The compound represented by formula (III) may also be produced by reacting ethyl 4-fluorobenzoate with a piperazine derivative with a basic atomic group, for example, pyrimidine or beonzimidazole, bonded thereto.
 less than Step 3 greater than 
The carboxylic ester represented by formula (III) may be hydrolyzed, followed by the formation of an amide bond to produce a compound represented by formula (IV). More specifically, a free carboxyl group prepared by hydrolysis with an alkali according to a conventional method is reacted with an amine represented by formula
R6HNCHR7CHR8COOR9
wherein R6, R7, R8, and R9 are as defined in formula (I)
to perform condensation reaction, thereby producing the amide compound represented by formula (IV).
Among the compounds represented by formula (IV), compounds having an optionally substituted pyrimidine ring may be, if necessary, reduced to a corresponding tetrahydropyrimidine.
In the condensation reaction, a condensing agent, such as dicyclohexylcarbodiimide, diisopropylcarbodiimide, or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hdyrochloride, may be used either solely or in combination with a peptide synthesis reagent, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, or benzotriazol-1-yloxytri(dimethylamino)phosphonium hexafluorophosphate. The combination of these reagents permits the desired condensation reaction to proceed with high efficiency. The use of a combination of 1 to 3 equivalents of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride with 1 to 2 equivalents of 1-hydroxybenzotriazole is preferred from the viewpoint of optimizing the yield.
Reaction solvents usable in the condensation reaction include dimethylformamide, dioxane, and tetrahydrofuran. Among them, dimethylformamide is preferred. The reaction may be carried out at 0 to 80xc2x0 C., preferably 20 to 60xc2x0 C.
In the condensation reaction, a tertiary amine, such as diisopropylethylamine, N-methylmorpholine, dimethylaminopyridine, or triethylamine, may be added as an organic base from the viewpoint of improving the yield. Among these tertiary amines, N-methylmorpholine is preferably added in an amount of 2 to 10 equivalents.
For the production of the compound represented by formula (IV) from the compound represented by formula (II) as the starting compound, the scheme represents, as a representative embodiment, the process which produces the contemplated compound through the compound represented by formula (III). However, the process, which produces the compound represented by formula (IV) from the compound represented by formula (II), is not limited to the above. Specifically, the compound represented by formula (IV) may be produced by previously protecting the secondary amine in the piperazine derivative portion of the compound represented by formula (II), converting the benzoic acid ester to a free carboxyl group, forming an amide bond, removing the protective group in the piperazine derivative portion, and introducing a basic atomic group, for example, pyrimidine or benzimidazole, into the secondary amine (see intermediate 20 and Example 34).
 less than Step 4 greater than 
The carboxylic acid ester represented by formula (III) may be converted to a corresponding aldehyde through one or two steps, followed by reductive amination to produce the compound represented by formula (V). For example, a free aldehyde group prepared through reduction and oxidation is reductively reacted with an amine represented by
R6HNCHR7CHR8COOR9
wherein R6, R7, R8, and R9 are as defined in formula (I)
to produce the amine represented by formula (V).
In the scheme, the carboxylic acid ester represented by formula (III) may be converted to a corresponding aldehyde by a conventional or novel method. Specifically, the corresponding aldehyde may be produced in one step by a suitable reduction reaction of the carboxylic acid ester. Alternatively, the carboxylic acid ester may be first suitably reduced to prepare a primary alcohol which is then suitably oxidized to produce the contemplated aldehyde. The process for producing the contemplated aldehyde in two steps will be exemplified.
A hydride reducing reagent, for example, two to three equivalents of diisobutylaluminum hydride, is allowed to act on the carboxylic acid ester as the compound represented by formula (III) in an aprotic solvent, for example, methylene chloride, at low temperature to convert the carboxylic acid ester to a corresponding benzyl alcohol. Next, the alcohol may be oxidized with an oxidizing reagent, such as manganese dioxide, chromium oxide, pyridinium chlorochromate, or pyridinium dichromate, in an organic solvent inert to the oxidation reaction to convert the alcohol to the corresponding aldehyde, preferably reacted with active manganese dioxide in ethyl acetate at room temperature, to produce the contemplated aldehyde.
Reducing reagents usable in the reductive amination reaction include sodiumboroncyanohydride, sodiumboronhydride, and sodiumborontriacetoxyhydride. Among them, sodiumboroncyanohydride is preferably used in an amount of 1 to 5 equivalents. Reaction solvents usable herein include dimethylformamide, methylene chloride, methanol, and acetic acid. The addition of a minor amount of acetic acid to a mixed solvent composed of methylene chloride and methanol to adjust the hydrogen ion concentration (pH) of the reaction solution to 3 to 4 is preferred. The reaction temperature is suitably 0 to 30xc2x0 C., preferably 20 to 25xc2x0 C.
The compounds represented by formula (V) prepared by the reductive amination, compounds, wherein R6 represents a group other than the hydrogen atom, may be produced by the step of other reaction than described above. Specifically, the free aldehyde group may be reductively reacted with an amine represented by
H2NCHR7CHR8COOR9
wherein R7, R8, and R9 are as defined in formula (I),
to produce, among the compounds represented by formula (V), a compound wherein R6 represents a hydrogen atom. Thereafter, the product may be further reductively aminated to introduce an alkyl, alkenyl, or aralkyl group into R6. The introduction of the alkyl, alkenyl, or aralkyl group into R6 is not always carried out for the compound represented by formula (V) in the scheme. Specifically, the introduction of the alkyl, alkenyl, or aralkyl group into R6 may be carried out for the compound represented by formula (VI) in the scheme (see Examples 23, 25, and 26).
In this reaction, R9 in xe2x80x94COOR9 corresponding to the carboxylic acid ester portion of the amine may be a hydrogen atom.
 less than Steps 5 and 6 greater than 
The carboxylic acid ester portion in the compound represented by formula (IV) or (V) in the scheme may be optionally converted to a free carboxyl group to produce the compound represented by formula (VI).
The carboxylic acid ester portion in the compound represented by formula (IV) or (V) may be converted to the contemplated free carboxyl group by a conventional method, for example, by hydrolysis with an alkali, hydrolysis with an acid, or reaction with an acid. The deesterification reaction may be achieved by a novel method without any restriction or limitation.
The compound represented by formula (IV) or (V) as such is an orally administrable integrin xcex1vxcex23 antagonist and/or GP IIb/IIIa antagonist. Therefore, the step of converting the carboxylic acid ester to the free carboxyl group is not always necessary.
Among the compounds represented by formula (VI), compounds having an optionally substituted pyrimidine ring may be optionally reduced to a corresponding tetrahydropyrimidine. The reduction may be carried by a conventional method. Examples of reduction methods usable herein include catalytic reduction in the presence of a catalyst, such as palladium-carbon, ruthenium-carbon, rhodium-carbon, palladium oxide, platinum oxide, ruthenium oxide, rhodium platinum oxide complex, rhodium aluminum oxide complex, Raney nickel, or palladium black, and a reaction, for example, with metallic sodium or metallic lithium in liquid ammonia. Preferably, the reduction is carried out in an acidic solvent, for example, in acetic acid acidified with hydrochloric acid, in the presence of palladium-carbon with hydrogen under normal or applied pressure.
In the scheme, for example, the compound represented by formula (III) is first converted to the compound represented by formula (IV) to form an amide bond, followed by reduction of an optionally substituted pyrimidine ring in the compound represented by formula (VI). However, for example, a basic functional group, for example, an optionally substituted pyrimidine ring, bonded to the secondary amino group of the piperazine derivative among the compound represented by formula (III) may be reduced followed by amide bond formation.
In the compounds represented by formula (IV), (V), and (VI) in the scheme, functional groups, which have been constructed in the molecule, for example, R4, R5, R7, and R8, may be optionally converted. Regarding the conversion of R8 in the compound represented by formula (VI), reference may be made to Examples 29, 30, 44, 47, 68, 69, 75, 76, 80, 81, and 84.
The compound represented by formula (I), wherein X represents CH and Z represents N, may be produced, for example, by reacting isonipecotic acid with 4-fluorobenzoic acid according to step 1 to prepare the phenylpiperidine derivative corresponding to formula (II) which is then subjected to steps 2 to 5. Group A may be introduced, for example, by reacting, before the reaction of isonipecotic acid with 4-fluorobenzoic acid, isonipecotic acid with 1,2-phenylenediamine under acidic conditions (for example, in the presence of concentrated hydrochloric acid or polyphosphoric acid) at a temperature of 100 to 200xc2x0 C., preferably 180xc2x0 C.
The compound represented by formula (I), wherein X represents N and Z represents CH, may be produced from 4-bromobenzyl alcohol with a protected hydroxyl group according to the method described in WO 94/12181. More specifically, the phenylpiperidine derivative corresponding to formula (II) may be produced by (1) reacting 4-bromobenzyl alcohol with lithium introduced thereinto (with a protected hydroxyl group) with N-Boc-4-piperidone to prepare a phenylpiperidine derivative, (2) reductively removing the resultant hydroxyl group, (3) removing the protective group from the protected hydroxyl group, (4) esterifying the deprotected hydroxyl group, and (5) removing the Boc group. The compound represented by formula (I), wherein X represents N and Z represents CH, may be produced from this phenylpiperidine derivative through steps 2 to 5.
Use of compounds/pharmaceutical composition
The compounds according to the present invention have potent integrin xcex1vxcex23 antagonistic activity, as demonstrated in Pharmacological Test Example 1. The integrin xcex1vxcex23 mediates cardiovascular diseases such as acute myocardial infarction, neointima formation hypertrophy, restenosis after PTCA/stent operation, unstable angina, acute coronary syndrome, angina pectoris after PTCA/stent operation, or arterial sclerosis, particularly atherosclerosis; angiogenesis-related diseases such as diabetic retinopathy, diabetic vascular complication, or vascular grafting; cerebrovascular diseases such as cerebral infarction; cancers such as solid tumors or metastasis thereof; immunological diseases such as arthritis, particularly rheumatic arthritis; and osteopathy such as osteoporosis, hypercalcemia, periodontitis, hyperparathyroidism, periarticular sore, or Paget""s diseases (DN and P, 10 (8), 456 (1997)). Accordingly, the compounds according to the present invention can be used in the treatment of these diseases. The term xe2x80x9ctherapyxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d as used herein includes xe2x80x9cpreventionxe2x80x9d or xe2x80x9cprophylaxis.xe2x80x9d
As described in Pharmacological Test Example 2, the compounds according to the present invention have GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity. Therefore, the compounds according to the present invention can be used in the treatment of platelet thrombosis and thromboembolism during and after the treatment of thrombolysis and after angioplasty of the coronary artery and other arteries and after bypassing of the coronary artery, the improvement of peripheral circulating blood stream, and the inhibition of blood clotting during extracorporeal circulation. Furthermore, the compounds according to the present invention can be used in the treatment of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome (Gendai Iryo, 29, (11), 2753 (1997)).
Not only compounds represented by formula (I) wherein R9 represents an alkyl group, but also compounds represented by formula (I) wherein R9 represents a hydrogen atom, for example, compounds prepared in Examples 3 and 5, had excellent oral absorption in rats (data not shown). Therefore, any of the compounds, wherein R9 represents an alkyl group or a hydrogen atom, can be used in the treatment of the above diseases.
The compounds according to the present invention and pharmacologically acceptable salts and solvates thereof can be administered orally or parenterally by administration routes, for example, inhalation administration, rhinenchysis, instillation, subcutaneous administration, intravenous injection, intravenous drip infusion, intramuscular injection, rectal administration, or percutaneous administration, and thus may be formed into appropriate various dosage forms depending on oral or parenteral administration routes and administered to human and non-human animals.
The compounds according to the present invention may be formulated into, for example, oral preparation, such as tablets, capsules, granules, powders, pills, particulates, troches, syrups, or emulsions; liquids for external use such as inhalants, nasal drops, or eye drops; injections such as intravenous injections or intramuscular injections; intravenous drip infusions; preparations for rectal administrations; oleaginous suppositories; water-soluble suppositories; and liniments such as ointments depending upon applications thereof.
These various preparations may be prepared by conventional methods with commonly used components, for example, excipients, extenders, binders, humidifiers, disintegrants, surface active agents, lubricants, dispersants, buffers, preservatives, dissolution aids, antiseptics, flavoring agents, analgesic agents, stabilizers and the like. Non-toxic additives usable herein include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or a salt thereof, gum arabic, olive oil, propylene glycol, polyethylene glycol, syrup, petrolatum, glycerin, ethanol, citric acid, sodium chloride, sodium sulfite, sodium phosphate, ascorbic acid, and cyclodextrins.
The content of the compound according to the present invention in the medicament may vary according to the dosage form. In general, however, the content is generally 1 to 70% by weight, preferably 5 to 50% by weight, based on the whole composition. The dose for the treatment and prevention of coronary diseases may be appropriately determined in consideration of, for example, the dosage route and the age, sex and severity of condition of patients, and the preparation may be administered usually in an amount of about 0.1 to 2,000 mg, preferably about 5 to 400 mg per day per adult. This dose is administered at a time daily, divided doses of several times daily, or at a time every several days.